Vitamin D insufficiency is a known susceptibility factor for multiple sclerosis (MS), but it is uncertain if it also influences the prognosis of individuals who already have the disease. While vitamin D supplementation in the animal model of MS improves clinical outcomes, well-designed studies in humans are lacking. A vitamin D response element was recently identified in the promoter region of HLA-DRB1*15, the gene believed to be critical to initiating the autoimmune response in MS, and vitamin D increases the expression of the gene in vitro. These findings suggest that vitamin D supplementation could even be harmful in established MS. While physician groups are beginning to advocate for widespread vitamin D supplementation, the most appropriate vitamin D dose is not known. Patients with MS who receive oral vitamin D supplementation may not attain the expected increase in serum 25-hydroxyvitamin D3 levels, and a polymorphism in a key enzyme in vitamin D metabolism is associated with increased MS risk, suggesting potential pharmacokinetic differences. We propose to capitalize on a large, extant MS cohort with prospectively-collected clinical and imaging data acquired annually for five years to determine if vitamin D status is associated with subsequent clinical or brain MRI evidence of increased inflammatory activity or accelerated neurodegeneration, two key pathologic processes in MS. We will also conduct a pilot study of vitamin D supplementation to assess if the pharmacokinetic or immunologic response differs in MS patients and healthy subjects. Finally, we will evaluate the association of vitamin D levels and supplementation with the expression of HLA-DRB1 and HLA-DRB5, which have been correlated with MS phenotype. This feasible and cost-effective project will provide rationale for future mechanistic studies of vitamin D in MS and for well-designed clinical trials. MS is a complex chronic neurologic disease, the study of which requires the integration of many disciplines. My career development plan includes training in advanced biostatistics and epidemiology, nutrition, immunology, genetics and neuroimaging, all of which I need to establish myself as an independent clinical researcher in MS. My long-term goal is to integrate these disciplines to identify modifiable environmental prognostic factors in MS and to explore the mechanisms by which they influence its course. The MS program at the University of California, San Francisco consists of a collaborative network of clinical, neuroimaging, genetics, and immunology researchers who will provide a rich environment in which I will conduct the proposed career development and research plans.